Piperazino-derivatives and their use as pde4 inhibitor

ABSTRACT

The compounds of formula I, in which R1, R2, R3, A, X, s and R9 have the meanings as given in the description are novel effecfive PDE4 inhibitors.

FIELD OF APPLICATION OF THE INVENTION

[0001] The invention relates to novel piperazino-derivatives, which areused in the pharmaceutical industry for the production of medicaments.

KNOWN TECHNICAL BACKGROUND

[0002] International Patent Applications WO98/31674, WO99/31071,WO99/31090 and WO99/47505 disclose phthalazinone derivatives havingselective PDE4 inhibitory properties. In the International patentapplication WO01/19818 phthalazinone derivatives with PDE3/4 inhibitoryproperties are disclosed. In the International Patent ApplicationWO94/12461 and in the European Patent Application EP 0 763 5343-aryl-pyridazin-6-one and arylalkyl-diazinone derivatives are describedas selective PDE4 inhibitors.

DESCRIPTION OF THE INVENTION

[0003] It has now been found that the piperazino-derivatives, which aredescribed in greater details below, have surprising and particularlyadvantageous properties.

[0004] The invention thus relates to compounds of formula I

[0005] in which

[0006] R1 and R2 are both hydrogen or together form an additional bond,

[0007] R3 represents a benzene derivative of formula (a) or (b)

[0008] wherein

[0009] R4 is 1-4C-alkoxy or 1-4C-alkoxy which is completely orpredominantly substituted by fluorine,

[0010] R5 is 1-8C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxy, or1-4C-alkoxy which is completely or predominantly substituted byfluorine,

[0011] R6 is 1-4C-alkoxy, 3-5C-cycloalkoxy, 3-5C-cycloalkylmethoxy, or1-4C-alkoxy which is completely or predominantly substituted byfluorine,

[0012] R7 is 1-4C-alkyl and

[0013] R8 is hydrogen or 1-4C-alkyl,

[0014] or wherein

[0015] R7 and R8 together and with inclusion of the two carbon atoms, towhich they are bonded, form a spiro-linked 5-, 6- or 7-memberedhydrocarbon ring, optionally interrupted by an oxygen or sulphur atom,

[0016] A is a bond or methylene (—CH₂—),

[0017] R9 is —C(O)R10, —(CH₂)_(m)—C(O)R11, —(CH₂)_(n)R12, Aryl, Hetaryl,phenylprop-1-en-3-yl or 1-methylpiperidin-4-yl,

[0018] R10 hydrogen, 1-4C-alkyl, —OR13, furanyl, indolyl, phenyl,pyridyl, phenyl substituted by R16 and/or R17 or pyridyl substituted byR18 and/or R19,

[0019] R11 is —N(R14)R15,

[0020] R12 is —N(R14)R15, tetrahydrofuranyl or pyridinyl,

[0021] R13 is 1-4C-alkyl,

[0022] R14 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl or3-7C-cycloalkylmethyl,

[0023] R15 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl or3-7C-cycloalkylmethyl, or R14 and R15 together and with inclusion of thenitrogen atom to which they are bonded, form a 4-morpholinyl-,1-pyrrolidinyl-, 1-piperidinyl- or 1-hexahydroazepinyl-ring,

[0024] Aryl is phenyl, pyridyl, pyrimidinyl, phenyl substituted by R16and/or R17, pyridyl substituted by R18 and/or R19,

[0025] R16 is halogen, nitro, 1-4C-alkyl, trifluoromethyl or1-4C-alkoxy,

[0026] R17 is halogen or 1-4C-alkyl,

[0027] R18 is halogen, nitro, 1-4C-alkyl, trifluoromethyl or1-4C-alkoxy,

[0028] R19 is halogen or 1-4C-alkyl,

[0029] Hetaryl is indol-4-yl, 2-methyl-quinolin-4-yl,5-chloro-6-oxo-1-phenyl-1,6-dihydro-pyridazin-4-yl,3-phenyl-1,2,4-thiadiazol-5-yl or 3-o-tolyl-1,2,4-thiadiazol-5-yl,

[0030] n is an integer from 1 to 4,

[0031] m is an integer from 1 to 4,

[0032] s is an integer from 1 to 2,

[0033] X is —C(O)— or —S(O)₂—,

[0034] and the salts of these compounds.

[0035] 1-4C-Alkyl is a straight-chain or branched alkyl radical having 1to 4 carbon atoms. Examples are the butyl, isobutyl, sec-butyl,tert-butyl, propyl, isopropyl, ethyl and methyl radicals.

[0036] 1-4C-Alkoxy is a radical which, in addition to the oxygen atom,contains a straight-chain or branched alkyl radical having 1 to 4 carbonatoms. Alkoxy radicals having 1 to 4 carbon atoms which may be mentionedin this context are, for example, the butoxy, isobutoxy, sec-butoxy,tert-butoxy, propoxy, isopropoxy, ethoxy and methoxy radicals.

[0037] 1-8C-Alkoxy is a radical which, in addition to the oxygen atom,contains a straight-chain or branched alkyl radical having 1 to 8 carbonatoms. Aikoxy radicals having 1 to 8 carbon atoms which may be mentionedin this context are, for example, the octytoxy, heptyloxy, isoheptyloxy(5-methyihexyloxy), hexyloxy, isohexyloxy (4-methylpentyloxy),neohexyloxy (3,3-dimethylbutoxy), pentyloxy, isopentyloxy(3-methylbutoxy), neopentyloxy (2,2-dimethylpropoxy), butoxy, isobutoxy,sec-butoxy, tert-butoxy, propoxy, isopropoxy, ethoxy and methoxyradicals.

[0038] Halogen within the meaning of the present invention is bromine,chlorine or fluorine.

[0039] 3-7C-Cycloalkoxy stands for cyclopropyloxy, cyclobutyloxy,cyclopentyloxy, cyclohexyloxy or cycloheptyloxy, of whichcyclopropyloxy, cyclobutyloxy and cyclopentyloxy are preferred.

[0040] 3-7C-Cycloalkylrmethoxy stands for cyclopropylmethoxy,cyclobutylmethoxy, cyclopentytmethoxy, cyclohexylmethoxy orcycloheptylmethoxy, of which cyclopropylmethoxy, cyclobutylmethoxy andcyclopentylmethoxy are preferred.

[0041] 3-5C-Cycloalkoxy stands for cyclopropytoxy, cyclobutyloxy andcyclopentyloxy.

[0042] 3-5C-Cycloalkylmethoxy stands for cyclopropylmethoxy,cyclobutylmethoxy and cyclopentylmethoxy.

[0043] 1-4C-Alkoxy which is completely or predominantly substituted byfluorine is, for example, the 2,2,3,3,3-pentafluoropropoxy, theperfluoroethoxy, the 1,2,2-trifluoroethoxy and in particular the1,1,2,2-tetrafluoroethoxy, the 2,2,2-trifluoroethoxy, thetrifluoromethoxy and the difluoromethoxy radical, of which thedifluoromethoxy radical is preferred. “Predominantly” in this connectionmeans that more than half of the hydrogen atoms of the 1-4C-alkoxy groupare replaced by fluorine atoms.

[0044] As spiro-linked 5-, 6- or 7-membered hydrocarbon rings,optionally interrupted by an oxygen or sulphur atom, may be mentionedthe cyclopentane, cyclohexane, cycloheptane, tetrahydrofuran,tetrahydropyran and the tetrahydrothiophen ring.

[0045] If R1 and R2 together form an additional bond, then the carbonatoms to which R1 and R2 are attached are linked to one another via adouble bond.

[0046] Suitable salts for compounds of the formula I—depending onsubstitution—are all acid addition salts or all salts with bases.Particular mention may be made of the pharmacologically tolerableinorganic and organic acids and bases customarily used in pharmacy.Those suitable are, on the one hand, water-soluble and water-insolubleacid addition salts with acids such as, for example, hydrochloric acid,hydrobromic acid, phosphoric acid, nitric acid, sulphuric acid, aceticacid, citric acid, D-gluconic acid, benzoic acid,2-(4-hydroxybenzoyl)benzoic acid, butyric acid, sulphosalicylic acid,maleic acid, lauric acid, malic acid, fumaric acid, succinic acid,oxalic acid, tartaric acid, embonic acid, stearic acid, toluenesulphonicacid, methanesulphonic acid or 3-hydroxy-2-naphthoic acid, the acidsbeing employed in salt preparation—depending on whether a mono- orpolybasic acid is concerned and depending on which salt is desired—in anequimolar quantitative ratio or one differing therefrom.

[0047] On the other hand, salts with bases are—depending onsubstitution—also suitable. As examples of salts with bases arementioned the lithium, sodium, potassium, calcium, aluminium, magnesium,titanium, ammonium, meglumine or guanidinium salts, here, too, the basesbeing employed in salt preparation in an equimolar quantitative ratio orone differing therefrom.

[0048] Pharmacologically intolerable salts, which can be obtained, forexample, as process products during the preparation of the compoundsaccording to the invention on an industrial scale, are converted intopharmacologically tolerable salts by processes known to the personskiiied in the art.

[0049] According to expert's knowledge the compounds of the invention aswell as their salts may contain, e.g. when isolated in crystalline form,varying amounts of solvents. Included within the scope of the inventionare therefore all solvates and in particular all hydrates of thecompounds of formula I as well as all solvates and in particular allhydrates of the salts of the compounds of formula I.

[0050] Compound of formula I to be emphasized are those in which

[0051] R1 and R2 are both hydrogen or together form an additional bond,

[0052] R3 represents a benzene derivative of formula (a) or (b)

[0053] wherein

[0054] R4 is 1-2C-alkoxy or 1-2C-alkoxy which is completely orpredominantly substituted by fluorine,

[0055] R5 is 1-4C-alkoxy,

[0056] R6 is 1 -2C-alkoxy or 1-2C-alkoxy which is completely orpredominantly substituted by fluorine,

[0057] R7 is methyl and

[0058] R8 is hydrogen,

[0059] or wherein

[0060] R7 and R8 together and with inclusion of the two carbon atoms, towhich they are bonded, form a spiro-linked cyclopentane, cyclohexane,tetrahydrofurane or tetrahydropyran ring,

[0061] A is a bond or methylene (—CH₂—),

[0062] R9 is —C(O)R10, —(CH₂)_(m)—C(O)R11, —(CH₂),R12, Aryl, Hetaryl,phenylprop-1-en-3-yl or 1-methylpiperidin-4-yl,

[0063] R10 hydrogen, 1-4C-alkyl, —OR13, furanyl, indolyl, pyridyl orpyridyl substituted by R18 and/or R19,

[0064] R11 is —N(R14)R15,

[0065] R12 is —N(R14)R15, tetrahydrofuranyl or pyridinyl,

[0066] R13 is 1-4C-alkyl,

[0067] R14 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl or3-7C-cycloalkylmethyl,

[0068] R15 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl or3-7C-cycloalkylmethyl,

[0069] or R14 and R15 together and with inclusion of the nitrogen atomto which they are bonded, form a 4-morpholinyl-, 1-pyrrolidinyl-,1-piperidinyl- or 1-hexahydroazepinyl-ring,

[0070] Aryl is phenyl, pyridyl, pyrimidinyl, phenyl substituted by R16and/or R17, pyridyl substituted by R18 and/or R19,

[0071] R16 is halogen, nitro, 1-4C-alkyl, trifluoromethyl or1-4C-alkoxy,

[0072] R17 is halogen or 1-4C-alkyl,

[0073] R18 is halogen, nitro, 1-4C-alkyl, trifluoromethyl or1-4C-alkoxy,

[0074] R19 is halogen or 1-4C-alkyl,

[0075] Hetaryl is indol-4-yl, 2-methyl-quinolin-4-yl,5-chloro-6-oxo-1-phenyl-1,6-dihydro-pyridazin-4-yl,3-phenyl-1,2,4-thiadiazol-5-yl or 3-o-tolyl-1,2,4-thiadiazol-5-yl,

[0076] n is an integer from 1 to 4,

[0077] m is an integer from 1 to 4,

[0078] s is 1,

[0079] X is —C(O)— or —S(O)₂—,

[0080] and the salts of these compounds.

[0081] Preferred compounds of formula I are those in which

[0082] R1 and R2 together form an additional bond,

[0083] R3 represents a benzene derivative of formula (a) or (b)

[0084] wherein

[0085] R4 is methoxy or ethoxy,

[0086] R5 is methoxy or ethoxy,

[0087] R6 is methoxy,

[0088] R7 is methyl and

[0089] R8 is hydrogen,

[0090] or wherein

[0091] R7 and R8 together and with inclusion of the two carbon atoms, towhich they are bonded, form a cyclopentane or cyclohexan ring,

[0092] A is a bond or methylene (—CH₂—),

[0093] R9 is phenyl, pyrid-2-yl, pyrid4-yl, pyrimidin-2-yl,3-dimethylaminopropyl, 2-dimethylaminoethyl,dimethylaminocarbonylmethyl, furan-2-yl-methanoyl, formyl,ethoxycarbonyl, 5-nitropyridin-2-yl, 3,5-dichloropyridin-4-yl,2-(morpholin-4-yl)ethyl, 3-(morpholin4-yl)propyl,2-morpholin-4-yl-2-oxo-ethyl, 2-oxo-2-pyrrolidin-1-yl-ethyl,1H-indol-4-yl, tetrahydrofuran-2-ylmethyl, 2-(pyrrolidin-1-yl)ethyl,pyridin4-ylmethyl, 2-methyl-quinolin-4-yl, 1-methyl-piperidin-4-yl,5-trifluoromethyl-pyridin-2-yl,5-chloro-6-oxo-1-phenyl-1,6-dihydro-pyridazin-4-yl,3-phenyl-1,2,4-thiadiazol-5-yl, 3-o-tolyl-1,2,4-thiadiazol-5-yl or(E)-3-phenylallyl,

[0094] s is 1,

[0095] X is —C(O)— or —S(O)₂—,

[0096] and the salts of these compounds.

[0097] Particularly preferred compounds of formula I are those in which

[0098] R1 and R2 together form an additional bond,

[0099] R3 represents a benzene derivative of formula (a) or (b)

[0100] wherein

[0101] R4 is methoxy or ethoxy,

[0102] R5 is methoxy or ethoxy,

[0103] R6 is methoxy,

[0104] R7 is methyl and

[0105] R8 is hydrogen,

[0106] A is a bond,

[0107] R9 is phenyl, pyrid-2-yl, pyrid4-yl, 3-dimethylaminopropyl,2-dimethylaminoethyl, dimethylaminocarbonylmethyl, furan-2-yl-methanoyl,formyl, ethoxycarbonyl, 5-nitropyridin-2-yl, 3,5-dichloropyridin-4-yl,2-(morpholin4-yl)ethyl, 3-(morpholin-4-yl)propyl,2-morpholin4-yl-2-oxo-ethyl, 2-oxo-2-pyrrolidin-1-yl-ethyl,1H-indol-4-yl, tetrahydrofuran-2-ylmethyl, 2-(pyrrolidin-1-yl)ethyl,pyridin4-yl-methyl, 2-methyl-quinolin-4-yl, 1-methyl-piperidin-4-yl,5-trifluoromethyl-pyridin-2-yl,5-chloro-6-oxo-1-phenyl-1,6-dihydro-pyridazin-4-yl,3-phenyl-1,2,4-thiadiazol-5-yl, 3-o-tolyl-1,2,4-thiadiazol-5-yl or(E)-3-phenylallyl,

[0108] s is1,

[0109] X is —C(O)—,

[0110] and the salts of these compounds.

[0111] Further particularly preferred compounds of formula I are thosein which

[0112] R1 and R2 together form an additional bond,

[0113] R3 represents a benzene derivative of formula (b)

[0114] wherein

[0115] R6 is methoxy,

[0116] R7 is methyl and

[0117] R8 is hydrogen,

[0118] A is methylene (—CH₂—),

[0119] R9 is pyrimidin-2-yl, 3-dimethylaminopropyl or2-(morpholin-4-yl)ethyl,

[0120] s is1,

[0121] X is —C(O)—,

[0122] and the salts of these compounds.

[0123] A preferred embodiment of compounds of formula I are

[0124] (4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-{4-[1-(4-phenyl-piperazin-1-yl)-methanoyl]-phenyl}4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,

[0125](4aS,8aR)-4-(3,4-Diethoxyphenyl)2-{4-[1-(4-pyridin-2-yl-piperazin-1-yl)-methanoyl]-phenyl}-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,

[0126](4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-(4{-[4-(3-dimethylamino-propyl)-piperazin-1-yl]-methanoyl)phenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,

[0127] (4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-(4(l-[4-(l-furan-2-yl-methanoyl)-piperazin-1-yl]-methanoyl}-phenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,

[0128]4-(1-{4-[(4aS,8aR)-4-(3,4-Diethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-phenylomethanoyl)-piperazine-1-carbaldehyde,

[0129](cis)-4-(3,4-Diethoxyphenyl)2-[4-(4-pyridin-2-yl-piperazine-1-sulfonyl)-phenyl]4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,

[0130] 4-(1-{4-[(4aS,8aR)-4-(3,4-Diethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-phenyl}methanoyl)-piperazine-1-carboxylic acid ethylester,

[0131](4aS,8aR)-4-(7-methoxy-2,2-dimethyl-2,3-dihydro-benzofuran-4-yl)-2-(4-(1-[4-((E)-3-phenyl-allyl)-piperazin-1-yl]-methanoyl}-phenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,

[0132](4aS,8aR)-2-(4-(1-[4-(1-furan-2-yl-methanoyl)-piperazin-1-yl]-methanoyl)-phenyl)-4-(7-methoxy-2,2-dimethyl-2,3-dihydro-benzofuran4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,

[0133](4aS,8aR)-4-(7-Methoxy-2,2-dimethyl-2,3-dihydro-benzofuran-4-yl)-2-{4-[1-(4-phenyl-piperazin-1-yl)-methanoyl]-phenyl}4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,

[0134](4aS,8aR)-2-(4-({-[4-(3-Dimethylamino-propyl)-piperazin-1-yl]-methanoyl}-phenyl)-4-(7-methoxy-2,2-dimethyl-2,3-dihydro-benzofuran4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,

[0135] (4aS,8aR)-2-{4-[4-(5-Chloro-6-oxo-i-phenyl-1,6-dihydro-pyridazin4-yl)-piperazine-1-carbonyl]-phenyl}-4-(3,4-diethoxy-phenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,

[0136](4aS,8aR)4-(3,4-Dimethoxyphenyl)-2-(4-{-[4-(3-dimethylamino-propyl)-piperazin-1-yl]-methanoyl}-phenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,

[0137](4aS,8aR)-2-{4-[4-(2-Dimethylamino-ethylypiperazine-1-carbonyl]-phenyl}-4-(7-methoxy-2,2-dimethyl-2,3-dihydro-benzofuran4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,

[0138](4aS,8aR)-2-{4-[4-(3,5-Dichloropyridin4-yl)-piperazin-1-yl]-methanoyl)-phenyl}-4-(3,4-dimethoxyphenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,

[0139](4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-(4-{1-[4-(2-morpholin-4-yl-ethyl)-piperazin-1-yl]-methanoyl}-phenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,

[0140] (4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-(4-{1-[4-(3-phenyl-1,2,4-thiadiazol-5-yl)-piperazin-1-yl]-methanoyl}-phenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,

[0141](4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-(4-{1-[4-(5-nitro-pyridin-2-yl)-piperazin-1-yl]-methanoyl}phenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,

[0142](4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-(4-{1-14-(3-o-tolyl-1,2,4-thiadiazol-5-yl)-piperazin-1-yl]-methanoyl}phenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,

[0143](4aS,8aR4-(7-Methoxy-2,2-dimethyl-2,3-dihydro-benzofuran4-yl)-2-(4-{1-[4-(2-morpholin-4-yl-ethyl)-piperazin-1-yl]-methanoyl}-phenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,

[0144](4aS,8aR)-4-(3,4-Diethoxy-phenyl)2-(4-{1-[4-(1H-indol-4-yl)-piperazin-1-yl]-methanoyl}-phenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,

[0145](4aS,8aR)-4-(3,4-Diethoxy-phenyl)-2-(4-{1-[4-(3-morpholin-4-yl-propyl)-piperazin-1-yl]-methanoyl}-phenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,

[0146](4aS,8aR4-(3,4-Diethoxy-phenyl)-2-(4-{1-[4-(tetrahydro-furan-2-ylmethyl)-piperazin-1-yl]-methanoyl}-phenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,

[0147](4aS,8aR)-4-(3,4-Diethoxy-phenyl)-2-(4-{1-[4-(2-pyrrolidin-1-yl-ethyl)-piperazin-1-yl]-methanoyl}-phenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,

[0148](4aS,8aR)-4-(3,4-Diethoxy-phenyl)-2-{4-[1-(4-pyridin4-ylmethyl-piperazin-1-yl)-methanoyl]-phenyl}-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,

[0149](4aS,8aR)-4-(3,4-Diethoxy-phenyl)-2-(4-{1-[4-(2-methyl-quinolin-4-yl)-piperazin-1-yl]-methanoyl}-phenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,

[0150](4aS,8aR)-4-(3,4-Diethoxy-phenyl)-2-{4-[1-(4-pyridin4-yl-piperazin-1-yl)-methanoyl]-phenyl}4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,

[0151](4aS,8aR)-4-(3,4-Diethoxy-phenyl)-2-(4-{1-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-methanoyl}-phenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,

[0152](4aS,8aR)-4-(3,4-Diethoxy-phenyl-2-(4-{1-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-methanoyl}-phenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,

[0153]2-[4-(1-{4-[(4aS,8aR)-4-(3,4-Dimethoxy-phenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-phenyl}-methanoyl)-piperazin-1-yl]-N,N-dimethyl-acetamide,

[0154](4aS,8aR)-4-(3,4-Dimethoxy-phenyl)-2-(4-{1-[4-(2-morpholin-4-yl-2-oxo-ethyl)-piperazin-1-yl]-methanoyl}-phenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,

[0155](cis)-4-(7-Methoxy-2,2-dimethyl-2,3-dihydro-benzofuran-4-yl)-2-(4-{1-[4-(2-morpholin-4-yl-ethyl)-piperazin-1-yl]-methanoyl}-benzyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,

[0156](cis)-2-(4-(1-[4-(3-Dimethylamino-propyl)-piperazin-1-yl]-methanoyl)-benzyl)-4-(7-methoxy-2,2-dimethyl-2,3-dihydro-benzofuran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,

[0157](4aS,8aR)-4-(3,4-Dimethoxy-phenyl)-2-(4-{1-[4-(2-oxo-2-pyrrolidin-1-yl-ethyl)-piperazin-1-yl]-methanoyl}-phenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,

[0158](cis)-4-(7-Methoxy-2,2-dimethyl-2,3-dihydro-benzofuran-4-yl)-2-[4-(1-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-yl-methanoyl)benzyl]-4aa,5,8,8a-tetrahydro-2H-phthalazin-1-one,

[0159] and the salts of these compounds.

[0160] A special embodiment of the compounds of the present inventioninclude those compounds of formula I in which R1 and R2 together form anadditional bond, R4 and R5 are 1-2C-alkoxy, R6 is methoxy, R7 is methyl,R8 is hydrogen and s is 1.

[0161] Another special embodiment of the compounds of the presentinvention include those compounds of formula I in which R1 and R2together form an additional bond, R3 represents a benzene derivative offormula (a), R4 and R5 are 1-2C-alkoxy and s is 1.

[0162] A further special embodiment of the compounds of the presentinvention include those compounds of formula I in which A is a bond ands is 1.

[0163] Still another special embodiment of the compounds of the presentinvention include those compounds of formula I in which R1 and R2together form an additional bond, s is 1 and X is —C(O)—.

[0164] Another further special embodiment of the compounds of thepresent invention include those compounds of formula I in which R1 andR2 together form an additional bond, s is 1 and R3 represents a benzenederivative of formula (b), wherein R6 is methoxy.

[0165] Yet another special embodiment of the compounds of the presentinvention include those compounds of formula I in which R1 and R2together form an additional bond, s is 1, X is —C(O)— and R3 representsa benzene derivative of formula (b), wherein R6 is methoxy, R7 is methyland R8 is hydrogen.

[0166] The compounds of formula I are chiral compounds. Chiral centersexist in the compounds of formula I in the positions 4a and 8a. In caseR3 represents a benzene derivative of formula (b) there is one furtherchiral center in the dihydrofuran-ring, if the substituents —R7 and—CH₂R8 are not identical. However, preferred are in this connectionthose compounds, In which the substituents —R7 and —CH₂R8 are identicalor together and with inclusion of the two carbon atoms to which they arebonded form a spiro-connected 5-, 6- or 7-membered hydrocarbon ring.

[0167] Therefore the invention includes all conceivable purediastereomers and pure enantiomers of the compounds of formula I, aswell as all mixtures thereof independent from the ratio, including theracemates. Preferred are those compounds of formula I, in which thehydrogen atoms in the positions 4a and 8a are cis-configurated.Especially preferred in this connection are those compounds, in whichthe absolute configuration (according to the rules of Cahn, Ingold andPrelog) is S in the position 4a and R in the position 8a.

[0168] Racemates can be split up into the corresponding enantiomers bymethods known by a person skilled in the art. Preferably the racemicmixtures are separated into two diastereomers during the preparationwith the help of an optical active separation agent on the stage of thecyclohexanecarboxylic acids or the 1,2,3,6-tetrahydrobenzoic acids (forexample, starting compounds A8, A9 and A10). As separation agents may bementioned, for example, optical active amines such as the (+)- and (−)forms of 1-phenylethylamine[(R)-(+)-1-phenylethylamine=D-α-methylbenzylamine or(S)-(−)-1-phenylethylamine=L-α-methylbenzylamine) and ephedrine, theoptical active alkaloids quinine, cinchonine, cinchonidine and brucine.

[0169] The compounds according to the invention can be prepared, forexample, as described in Reaction scheme 1.

[0170] Reaction scheme 1 shows exemplarily the preparation of (4aS,8aR)-configurated compounds of formula I. The (4aR, 8aS)-configuratedcompounds of formula I can be prepared analogously using in the firstreaction step the antipodes of the optical amines shown in reactionscheme 1.

[0171] Starting from racemic (cis)-keto-1,2,3,4,5,6-hexahydrobenzoic- orracemic (cis)-keto-1,2,3,6-tetrahydrobenzoic acids of formula VI the twocis configurated enantiomeres are separated in form of theirdiastereomeric salts (compounds of formula V) with optical active aminessuch as the(+)- and (−)-forms of 1-phenylethylamine[(R)-(+)-1-phenylethylamine=D-α-methylbenzylamine or(S)-(−)-1-phenylethylamine=L-α-methylbenzylamine), ephedrine, theoptical active alkaloids quinine, cinchonine, cinchonidine and brucine.

[0172] In a second reaction step the compounds of formula V arecondensed with 4-hydrazinobenzoic acid or 4-hydrazino benzene sulfonicacid to give the compounds of formula III, in which A represents a bond.Altematively, the compounds of formula V are first reacted withhydrazine to give the compounds of formula IV which then are reactedwith 4-chloromethylbenzoic acid or 4-chloromethylbenzene sulfonic acidto give the compounds of formula III, in which A represents methylene(—CH₂—).

[0173] The compounds of formula III are activated by a chlorinationagent like, for example, phosphorpentachloride (→ compounds of formulaII) or alternative by a suitable carbodiimide like, for example, DCC orEDC, and then are converted with a piperazine substituted by R9 (or ahomopiperazine substituted by R9) to give the compounds of formula I.

[0174] Suitably, the conversions are carried out analogous to methodswhich are familiar per se to the person skilled in the art, for example,in the manner which is described in the following examples.

[0175] The substances according to the invention are isolated andpurified in a manner known per se, e.g. by distilling off the solvent invacuo and recrystallising the residue obtained from a suitable solventor subjecting it to one of the customary purification methods, such ascolumn chromatography on a suitable support material.

[0176] Salts are obtained by dissolving the free compound in a suitablesolvent (for example a ketone like acetone, methylethylketone, ormethylisobutylketone, an ether, like diethyl ether, tetrahydrofuran ordioxane, a chlorinated hydrocarbon, such as methylene chloride orchloroform, or a low molecular weight aliphatic alcohol, such asethanol, isopropanol) which contains the desired acid, or to which thedesired acid is then added. The salts are obtained by filtering,reprecipitating, precipitating with a non-solvent for the addition saltor by evaporating the solvent. Salts obtained can be converted bybasification into the free compounds which, in turn, can be convertedinto salts. In this manner, pharmacologically non-tolerable salts can beconverted into pharmacologically tolerable salts.

[0177] The following examples illustrate the invention in greaterdetail, without restricting it. As well, further compounds of formula I,of which the preparation is explicitly not described, can be prepared inan analogous way or in a way which is known by a person skilled in theart using customary preparation methods.

[0178] The compounds, which are mentioned in the examples as well astheir salts are preferred compounds of the invention.

EXAMPLES

[0179] Final Products

[0180] 1.(4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-{4-[1-(4-phenyl-piperazin-1-yl)-methanoyl]-phenyl}-4a,5,8,8a-tetrahydro-2H-phthalazin-1-onehydrochloride

[0181] A solution of 4 mmol of intermediate product A1 and 4 mmol ofPCl₅ in 50 ml of dichloromethane is stirred for 30 min after which thesolvent is evaporated. The residue is dissolved in 20 ml oftetrahydrofurane and added slowly to a solution of 3 mmol of1-phenylpiperazine in 20 ml of pyridine. After stirring the resultingmixture for 30 min, the solvent is evaporated and the residuepartitioned between aqueous sodium carbonate and ethyl acetate. Theorganic layer is dried over magnesium sulfate, after which a solution ofhydrochloric acid in diethyl ether is added. The precipitate is filteredoff and dried. M.p. 146-147° C.

[0182] 2.(4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-{4-[1-(4-pyridin-2-yl-piperazin-1-yl)-methanoyl]-phenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one

[0183] Prepared from intermediate product A1 and 1-(2-pyridyl)piperazineas described for compound 1. Cystallised from diethyl ether as the freebase. M.p.183-184° C.

[0184] 3.(4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-(4-{1-[4-(3-dimethylamino-propyl)-piperazin-1-yl]-methanoyl}-phenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-onedihydrochloride

[0185] Prepared from intermediate product A1 and1-(3-dimethylaminopropyl)piperazine as described for compound 1.Cystallised from diethyl ether as the free base. M.p. 248° C. (withdecomposition).

[0186] 4.(4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-(4-{1-[4-(1-furan-2-yl-methanoyl)-piperazin-1-yl]-methanoyl}-phenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one

[0187] Prepared from intermediate product A1 and1-(furan-2-yl-methanoyl)piperazine as described for compound 1.Cystallised from diethyl ether as the free base. M.p. 114-115° C.

[0188] 5.4-(1-{4-[(4aS,8aR)-4-(3,4-Diethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-phenyl-methanoyl)-piperazine-1-carbaldehyde

[0189] Prepared from intermediate product A1 and piperazinylcarbaldehydeas described for compound 1. Cystallised from diethyl ether as the freebase. M.p. 143-144° C.

[0190] 6.(cis)-4-(3,4-Diethoxyphenyl)-2-[4-(4-pyridin-2-yl-piperazine-1-sulfonyl)-phenyl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one

[0191] Prepared from intermediate product A5 and 1-(2-pyridyl)piperazineas described for compound 1. Cystallised from diethyl ether as the freebase. M.p. 181-182° C.

[0192] 7.4-(1-[4-[(4aS,8aR)-4-(3,4-Diethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-phenyl)-methanoyl)-piperazine-1-carboxylicacid ethyl ester

[0193] Prepared from intermediate product A1 and1-(ethoxycarbonyl)piperazine as described for compound 1. Cystallisedfrom diethyl ether as the free base. M.p. 146-147° C.

[0194] 8.(4aS,8aR)-4-(7-methoxy-2,2-dimethyl-2,3-dihydro-benzofuran-4-yl)-2-(4-{1-[4-((E)-3-phenyl-allyl)-piperazin-1-yl]-methanoyl}-phenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-onehydrochloride

[0195] A mixture of 2 mmol of intermediate product A2, 2 mmol of1-{(E)3-phenyl-allyl}-piperazine and 3 mmol of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride in 30 ml ofdimethylformamide is stirred for 18 h, after which the mixure is pooredinto aqueous sodium carbonate. This mixture is extracted with diethylether and the extract is dried over magnesium sulfate. Addition of asolution of hydrochloric acid in ether causes precipitation of the titlecompound. M.p. 230-231° C.

[0196] 9.(4aS,8aR)-2-(4-{1-[4-(1-furan-2-yl-methanoyl)-piperazin-1-yl]-methanoyl}-phenyl)-4-(7-methoxy-2,2dimethyl-2,3-dihydrobenzofuran-4-yl)-4a,5,8,8a-tetrahydro2-phthalazin-1-one

[0197] Prepared from intermediate product A2 and1-(furan-2-yl-methanoyl)-piperazine as described for compound 8.Crystallised from diethyl ether as the free base. M.p. 138-140° C.

[0198] 10.(4aS,8aR)-4-(7-Methoxy-2,2-dimethyl-2,3-dihydro-benzofuran-4-yl)-2-{4-[1-(4-phenyl-piperazin-1-yl)-methanoyl]-phenyl}-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one

[0199] Prepared from intermediate product A2 and 1-phenylpiperazine asdescribed for compound 8. Crystallised from diethyl ether as the freebase. M.p. 185-186° C.

[0200] 11.(4aS,8aR)-2-(4-{1-[4-(3-Dimethylamino-propyl)-piperazin-1-yl]-methanoyl}-phenyl)-4-(7-methoxy-2,2-dimethyl-2,3dihydro-benzofuran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-onedihydrochloride

[0201] Prepared from intermediate product A2 and1-(3-dimethylaminopropyl)-piperazine as described for compound 8. M.p.262° C. (with decomposition).

[0202] 12.(4aS,8aR)-2-{4-[4-(5-Chloro-6-oxo-1-phenyl-1,6-dihydro-pyridazin-4-yl)-piperazine-1-carbonyl]-phenyl}-4-(3,4-diethoxy-phenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one

[0203] Prepared from intermediate product A1 and1-(5-Chloro-6-oxo-1-phenyl-1,6-dihydro-pyridazin-4-yl)piperazine asdescribed for compound 8. Crystallised from methanol. M.p. 148-151° C.

[0204] 13.(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-(4-{1-[4-(3-dimethylamino-propyl)-piperazin-1-yl]-methanoyl}-phenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-onedihydrochloride

[0205] Prepared from intermediate product A6 and1-(3-dimethylaminopropyl)piperazine as described for compound 8. M.p.223-226° C.

[0206] 14.(4aS,8aR)-2-{4-[-(2-Dimethylamino-ethyl)-piperazine-1-carbonyl]-phenyl}-4-(7-methoxy-2,2-dimethy-2,3-dihydro-benzofuran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-onedihydrochloride

[0207] Prepared from intermediate product A2 and1-(2-dimethylaminoethyl)-piperazine as described for compound 8. M.p.245° C. (with decomposition).

[0208] 15.(4aS,8aR)-2-(4-{1-[4-(3.5-Dichloropyrldin-4-yl)-piperazin-1-yl]-methanoyl}-phenyl)-4-(3,4-dimethoxyphenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one

[0209] Prepared from intermediate product A6 and1-(3,5-Dichloropyridin-4-yl)piperazine as described for compound 8.Crystallised as the free base from methanol. M.p. 137-139° C.

[0210] 16.(4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-(4-{1-[4-(2-morpholin-4-yl-ethyl)-piperazin-1-yl]-methanoyl}-phenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-onedihydrochloride

[0211] Prepared from intermediate product A1 and1-{2-(4-morpholino)ethyl}piperazine as described for compound 8. M.p.255° C. (with decomposition).

[0212] 17.(4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-(4-{1-[4-(3-phenyl-1,2,4-thiadiazol-5-yl)-piperazin-1-yl]-methanoyl}-phenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one

[0213] Prepared from intermediate product A1 and1-(3-phenyl-1,2,4-thiadiazol-5-yl)-piperazine as described for compound8. Crystallised as the free base from diethyl ether. M.p. 168-169° C.

[0214] 18.(4aS,8aR)-4-(3,4-Diethoxyohenyl)-2-(4-{1-[4-(5-nitro-pyridin-2-yl)-piperazin-1-yl]-methanoyl}-phenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-onehydrochloride

[0215] Prepared from intermediate product A1 and1-(5-nitropyridin-2-yl)-piperazine as described for compound 8.M.p.117-118° C.

[0216] 19.(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-(4-{1-[4-(3-o-tolyl-1,2,4-thiadiazol-5-yl)-piperazin-1-yl]-methanoyl}-phenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-onehydrochloride

[0217] Prepared from intermediate product A1 and1-(3-o-tolyl-1,2,4-thiadiazol-5-yl)-piperazine as described for compound8. M.p. 115-118° C.

[0218] 20.(4aS,8aR)-4-(7-Methoxy-2,2-dimethyl-2,3-dihydro-benzofuran-4-yl)-2-(4-{1-[4-(2-morpholin-4-yl-ethyl)-piperazin-1-yl]-methanoyl}-phenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-onedihydrochloride

[0219] Prepared from intermediate product A2 and4-(2-piperazin-1-yl-ethyl)-morpholine as described for compound 8. M.p.271° C. (decomposes).

[0220] 21.(4aS,8aR)-4-(3,4-Diethoxy-phenyl)-2-[4-{1-[4-(1H-indol-4-yl)-piperazin-1-yl]-methanoyl}-phenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-onehydrochloride

[0221] Prepared from intermediate product A1 and 4-piperazin-1-yl-lH-indole as described for compound 8. M.p. 142-145° C.

[0222] 22.(4aS,8aR)-4-(3,4-Diethoxy-phenyl)-2-(4-{1-[4-(3-morpholin-4-yl-propyl)-piperazin-1-yl]-methanoyl}-phnyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-onedihydrochloride

[0223] Prepared from intermediate product A1 and4-(3-piperazin-1-yl-propyl)-morpholine as described for compound 8. M.p.170-171° C.

[0224] 23.(4aS,8aR)-4-(3,4-Diethoxy-phenyl)-2-(4-{1-[4-(tetrahydro-furan-2-ylmethyl)-piperazin-1-yl]-methanoyl}-phenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-onehydrochloride

[0225] Prepared from intermediate product A1 and1-(tetrahydro-furan-2-ylmethyl)-piperazine as described for compound 8.M.p. 131-133° C.

[0226] 24.(4aS,8aR)-4-(3,4-Diethoxy-phenyl)-2-(4-{1-[4-(2-pyrrolldin-1-yl-ethyl)-piperazin-1-yl]-methanoyl}-phenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-onedihydrochloride

[0227] Prepared from intermediate product A1 and1-(2-pyrrolidin-1-yl-ethyl)-piperazine as described for compound 8. M.p.185-186° C.

[0228] 25.(4aS,8aR)-4-(3,4-Diethoxy-phenyl)-2-{4-[1-(4-pyridin-4-ylmethyl-piperazin-1-yl)-methanoyl]-phenyl}-4a,5,8,8a-tetrahydro-2H-phthalazin-1-onedihydrochloride

[0229] Prepared from intermediate product A1 and1-pyridin-4-ylmethyl-piperazine as described for compound 8. M.p. 83-85°C.

[0230] 26.(4aS,8aR)-4-(3,4-Diethoxy-phenyl)-2-(4-{1-[4-(2-methyl-quinolin-4-yl)-piperazin-1-yl]-methanoyl}-phenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-onehydrochloride

[0231] Prepared from intermediate product A1 and2-methyl-4-piperazin-1-yl-quinoline as described for compound 8. M.p.203-206° C. (decomposes)

[0232] 27.(4aS,8aR)-4-(3,4-Diethoxy-phenyl)-2-(4-{1-(4-pyridin-4-yl-piperazin-1-yl)-methanoyl]-phenyl}-4a,5,8,8a-tetrahydro-2H-phthalazin-1-onehydrochloride

[0233] Prepared from intermediate product A1 and1-pyridin4-yl-piperazine as described for compound 8. M.p. 164-167° C.

[0234] 28.(4aS,8aR)-443,4-Diethoxy-phenyl)-2-(4-{1-[4-1-methyl-piperidin-4-yl)-piperazin-1-yl]-methanoyl}-phenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-onedihydrochloride

[0235] Prepared from intermediate product A1 and1-(1-methyl-piperidin-4-yl)-piperazine as described for compound 8. M.p.275° C. (decomposes)

[0236] 29.(4aS,8aR)-4-(3,4-Diethoxy-phenyl)-2-(4-{1-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-methanoyl}-phenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one

[0237] Prepared from intermediate product A1 and1-(5-trifluoromethyl-pyridin-2-yl)-piperazine as described for compound8. M.p. 121-123° C.

[0238] 30.2-[4-(1-{4-[(4aS,8aR)-4-(3,4-Dimethoxy-phenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-phenyl}-methanoyl)-piperazin-1-yl]-N,N-dimethyl-acetamidehydrochloride

[0239] Prepared from intermediate product A6 andN,N-dimethyl-2-piperazin-1-yl-acetamide as described for compound 8.M.p. 93-94° C.

[0240] 31.(4aS,8aR)-4(3,4-Dimethoxy-phenyl)-2-(4-{1-[4-(2-morpholin-4-yl-2-oxo-ethyl)-piperazin-1-yl]-methanoyl}-phenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-onehydrochloride

[0241] Prepared from intermediate product A6 and1-morpholin-4-yl-2-piperazin-1-yl-ethanone as described for compound 8.M.p. 168-169° C.

[0242] 32.(cis)-4-(7-Methoxy-2,2-dimethyl-2,3-dihydro-benzofuran-4-yl)-2-(4-{1-[4-(2-morpholin-4-yl-ethyl)-piperazin-1-yl]-methanoyl}-benzyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-onedihydrochloride

[0243] Prepared from intermediate product A11 and4-(2-piperazin-1-yl-ethyl)-morpholine as described for compound 8. M.p.210-211° C.

[0244] 33.(cis)-2-(4-{1-[4-(3-Dimethylamino-propyl)-piperazin-1-yl]-methanoyl}-benzyl)-4-(7-methoxy-2,2-dimethyl-2,3-dihydro-benzofuran-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-onedihydrochloride

[0245] Prepared from intermediate product A11 anddimethyl-(3-piperazin-1-yl-propyl)-amine as described for compound 8.M.p. 247-249° C.

[0246] 34.(4aS,8aR)-4-(3,4-Dimethoxy-phenyl)-2-(4-{1-[4-(2-oxo-2-pyrrolidin-1-yl-ethyl)-piperazin-1-yl]-methanoyl}-phenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-onehydrochloride

[0247] Prepared from intermediate product A6 and2-piperazin-1-yl-1-pyrrolidin-1-yl-ethanone as described for compound 8.M.p. 160-161° C.

[0248] 35.(cis)-4-(7-Methoxy-2,2-dimethyl-2,3-dihydro-benzofuran4-yl)-2-[4-(1-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-yl-methanoyl)-benzyl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-onedihydrochloride

[0249] Prepared from intermediate product A11 and3,4,5,6-Tetrahydro-2H-[1,2′]bipyrazinyl as described for compound 8.M.p. 124-126° C.

Starting Compounds and Intermediate Products

[0250] A1.(4aS,8aR)-4-(3,4-Diethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl}benzoicacid

[0251] A solution of 8 g of intermediate product A4 and 8 g of4-hydrazinobenzoic acid in a mixture of 100 ml of 1-propanol and 5 ml oftriethyl amine are refluxed for 18 h. After evaporating the solvent, theresidue is partitioned between diluted hydrochloric acid anddichloromethane. The organic layer is dried over magnesium sulphate andevaporated. The residue is purified by chromatography (ethyl acetate).Crystallisation from diethyl ether. M.p. 204 - 207° C.

[0252] A2.4-{(4aS,8aR)-4-(2,3-Dihydro-2,2-dimethyl-7-methoxybenzofuranyl)-1-oxo-4a,5,8,8a-tetrahydrophthalazin-2-yl}benzoicacid

[0253] A solution of 10 g of intermediate product A3, 10 g of4-hydrazinobenzoic acid and 3 g of pyridine hydrochloride in 50 ml ofpyridine are refluxed for 18 h. After evaporating the solution, theresidue is dissolved in ethyl acetate and washed 3 times with 1 Nhydrochloric acid. The solution is then dried over magnesium sulphateand evaporated. The title compound is crystallised from diethyl ether.M.p. 212 - 214° C.

[0254] A3.(1R,2S)-2-(2,3-Dihydro-2,2-dimethyl-7-methoxybenzofuran-4-carbonyl)-1,2,3,6-tetrahydrobenzoicacid (1R,2S)-4-)-ephedrine salt

[0255] A mixture of 10 mmol of starting compound A10 and 5 mmol of(1R,2S)-(−)-ephedrine in 150 ml of ethyl acetate is stirred for 18 hafter which the precipitate is filtered off and dried.

[0256] A4. (1R,2S)-2-(3,4-Diethoxybenzoyl)-1,2,3.6-tetrahydrobenzoicacid (−)-methylbenzylamine salt

[0257] A mixture of 10 mmol of starting compound A8 and 5 mmol ofL-α-methylbenzylamine in 100 ml of ethyl acetate is stirred for 18 hafter which the precipitate is filtered off and dried.

[0258] A5.(cis)-4-{4-(3,4-Diethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl}benzenesulfonicacid

[0259] A solution of 16 mmol of starting compound A8, 16 mmol of4-hydrazino benzene sulfonic acid and 5 ml of triethyl amine in 100 mlof 1-propanol is refluxed for 6 h. After evaporating, the residue isdissolved in 100 ml of acetic acid and refluxed for 2 h. Afterevaporating, the residue is partitioned between 1 N hydrochloric acidand ethyl acetate. The organic layer is dried over magnesium sulfate andevaporated. The title compound is crystallised from diethyl ether. M.p.65-69° C.

[0260] A6.(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-1-oxo4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl}benzoicacid

[0261] Prepared from intermediate product A7 as described for startingcompound A1. Crystallised from diethyl ether. M.p.185-186° C.

[0262] A7. (1R,2S)-2-(3,4-Dimethoxybenzoyl)-1,2,3,6-tetrahydrobenzoicacid (−)-α-methylbezylamine salt

[0263] Prepared analogously as described for intermediate product A4using starting compound A9 instead of A8.

[0264] A8. (cis)-2-(3,4-Diethoxybenzoyl)-1,2,3,6-tetrahydrobenzolc acid

[0265] Prepared as described in WO98/31674.

[0266] A9. (cis)-2-(3,4-Dimethoxybenzoyl)-1,2,3,6-tetrahydrobenzoic acid

[0267] Prepared as described in WO98/31674.

[0268] A10.(cis)-2-(2,3-Dihydro-2,2-dimethyl-7-methoxybenzofuran-4-carbonyl)-1,2,3,6-tetrahydrobenzoicacid

[0269] Prepared as described in WO99/31090.

[0270] A11.(cis)-4-[4-(7-Methoxy-2,2-dimethyl-2,3-dihydro-benzofuran4-yl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-ylmethyl]-benzoicacid

[0271] To a solution of 0.05 mole of(cis)-4-(7-Methoxy-2,2-dimethyl-2,3-dihydro-benzofuran4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one(starting compound A12) and 0.15 mole of sodium hydride in 100ml ofdimethylformamide is stirred at RT for 30 min, after which 0.05 mole of4-chloromethylbenzoic acid is added. This mixture is left stirring for18 h, after which it is poured into water. This solution is acidifiedwith hydrochloric acid and subsequently extracted with dichloromethane.The organic solution is dried over magnesium sulfate and evaporated. Thecompound is crystallized from diethyl ether. M.p. 219-220° C.

[0272] A12.(cis)-4-(7-Methoxy-2,2-dimethyl-2,3-dihydro-benzofuran4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one

[0273] Prepared as described in WO99/31090.

Commercial Utility

[0274] The compounds according to the invention have usefulpharmacological properties which make them industrially utilizable. Asselective cyclic nucleotide phosphodiesterase (PDE) inhibitors(specifically of type 4), they are suitable on the one hand as bronchialtherapeutics (for the treatment of airway obstructions on account oftheir dilating action but also on account of their respiratory rate- orrespiratory drive-increasing action) and for the removal of erectiledysfunction on account of their vascular dilating action, but on theother hand especially for the treatment of disorders, in particular ofan inflammatory nature, e.g. of the airways (asthma prophylaxis), of theskin, of the intestine, of the eyes, of the CNS and of the joints, whichare mediated by mediators such as histamine, PAF (platelet-activatingfactor), arachidonic acid derivatives such as leukotrienes andprostaglandins, cytokines, interleukins, chemokines, alpha-, beta- andgamma-interferon, tumor necrosis factor (TNF) or oxygen free radicalsand proteases. In this context, the compounds according to the inventionare distinguished by a low toxicity, a good enteral absorption (highbioavailability), a large therapeutic breadth and the absence ofsignificant side effects.

[0275] On account of their PDE-inhibiting properties, the compoundsaccording to the invention can be employed in human and veterinarymedicine as therapeutics, where they can be used, for example, for thetreatment and prophylaxis of the following illnesses: acute and chronic(in particular inflammatory and allergen-induced) airway disorders ofvarying origin (bronchitis, allergic bronchitis, bronchial asthma,emphysema, COPD); dermatoses (especially of proliferative, inflammatoryand allergic type) such as psoriasis (vulgaris), toxic and allergiccontact eczema, atopic eczema, seborrhoeic eczema, Lichen simplex,sunburn, pruritus in the anogenital area, alopecia areata, hypertrophicscars, discoid lupus erythematosus, follicular and widespreadpyodermias, endogenous and exogenous acne, acne rosacea and otherproliferative, inflammatory and allergic skin disorders; disorders whichare based on an excessive release of TNF and leukotrienes, for exampledisorders of the arthritis type (rheumatoid arthritis, rheumatoidspondylitis, osteoarthritis and other arthritic conditions), disordersof the immune system (AIDS, multiple sclerosis), graft versus hostreaction, allograft rejections, types of shock (septic shock, endotoxinshock, gram-negative sepsis, toxic shock syndrome and ARDS (adultrespiratory distress syndrome)) and also generalized inflammations inthe gastrointestinal region (Crohn's disease and ulcerative colitis);disorders which are based on allergic and/or chronic, immunologicalfalse reactions in the region of the upper airways (pharynx, nose) andthe adjacent regions (paranasal sinuses, eyes), such as allergicrhinitis/sinusitis, chronic rhinitis/sinusitis, allergic conjunctivitisand also nasal polyps; but also disorders of the heart which can betreated by PDE inhibitors, such as cardiac insufficiency, or disorderswhich can be treated on account of the tissue-relaxant action of the PDEinhibitors, such as, for example, erectile dysfunction or colics of thekidneys and of the ureters in connection with kidney stones. Inaddition, the compounds of the invention are useful in the treatment ofdiabetes insipidus and conditions associated with cerebral metabolicinhibition, such as cerebral senility, senile dementia (Alzheimer'sdisease), memory impairment associated with Parkinson's disease ormultiinfarct dementia; and also illnesses of the central nervous system,such as depressions or arteriosclerotic dementia.

[0276] The invention further relates to a method for the treatment ofmammals, including humans, which are suffering from one of theabovementioned illnesses. The method is characterized in that atherapeutically active and pharmacologically effective and tolerableamount of one or more of the compounds according to the invention isadministered to the ill mammal.

[0277] The invention further relates to the compounds according to theinvention for use in the treatment and/or prophylaxis of illnesses,especially the illnesses mentioned.

[0278] The invention also relates to the use of the compounds accordingto the invention for the production of medicaments which are employedfor the treatment and/or prophylaxis of the illnesses mentioned.

[0279] The invention furthermore relates to medicaments for thetreatment and/or prophylaxis of the illnesses mentioned, which containone or more of the compounds according to the invention.

[0280] Additionally, the invention relates to an article of manufacture,which comprises packaging material and a pharmaceutical agent containedwithin said packaging material, wherein the pharmaceutical agent istherapeutically effective for antagonizing the effects of the cyclicnucleotide phosphodiesterase of type 4 (PDE4), ameliorating the symptomsof an PDE4-mediated disorder, and wherein the packaging materialcomprises a label or package insert which indicates that thepharmaceutical agent is useful for preventing or treating PDE4-mediateddisorders, and wherein said pharmaceutical agent comprises one or morecompounds of formula I according to the invention. The packagingmaterial, label and package insert otherwise parallel or resemble whatis generally regarded as standard packaging material, labels and packageinserts for pharmaceuticals having related utilities.

[0281] The medicaments are prepared by processes which are known per seand familiar to the person skilled in the art. As medicaments, thecompounds according to the invention (=active compounds) are eitheremployed as such, or preferably in combination with suitablepharmaceutical auxiliaries and/or excipients, e.g. in the form oftablets, coated tablets, capsules, caplets, suppositories, patches (e.g.as TTS), emulsions, suspensions, gels or solutions, the active compoundcontent advantageously being between 0.1 and 95% and where, by theappropriate choice of the auxiliaries and/or excipients, apharmaceutical administration form (e.g. a delayed release form or anenteric form) exactly suited to the active compound and/or to thedesired onset of action can be achieved.

[0282] The person skilled in the art is familiar with auxiliaries orexcipients which are suitable for the desired pharmaceuticalformulations on account of his/her expert knowledge. In addition tosolvents, gel formers, ointment bases and other active compoundexcipients, for example antioxidants, dispersants, emulsifiers,preservatives, solubilizers, colorants, complexing agents or permeationpromoters, can be used.

[0283] The administration of the medicaments according to the inventionmay be performed in any of the generally accepted modes ofadministration available in the art. Illustrative examples of suitablemodes of administration include intravenous, oral, nasal, parenteral,topical, transdermal and rectal delivery. Oral and intravenous deliveryare preferred.

[0284] For the treatment of disorders of the respiratory tract, thecompounds according to the invention are preferably also administered byinhalation in the form of an aerosol; the aerosol particles of solid,liquid or mixed composition preferably having a diameter of 0.5 to 10μm, advantagously of 2 to 6 μm.

[0285] Aerosol generation can be carried out, for example, bypressure-driven jet atomizers or ultrasonic atomizers, butadvantageously by propellant-driven metered aerosols or propellant-freeadministration of micronized active compounds from inhalation capsules.

[0286] Depending on the inhaler system used, in addition to the activecompounds the administration forms additionally contain the requiredexcipients, such as, for example, propellants (e.g. Frigen in the caseof metered aerosols), surface-active substances, emulsifiers,stabilizers, preservatives, flavorings, fillers (e.g. lactose in thecase of powder inhalers) or, if appropriate, further active compounds.

[0287] For the purposes of inhalation, a large number of apparatuses areavailable with which aerosols of optimum particle size can be generatedand administered, using an inhalation technique which is as right aspossible for the patient. In addition to the use of adaptors (spacers,expanders) and pear-shaped containers (e.g. Nebulatorg, Volumatic®), andautomatic devices emitting a puffer spray (Autohaler®), for meteredaerosols, in particular in the case of powder inhalers, a number oftechnical solutions are available (e.g. Diskhaler®, Rotadisk®,TurbohalerS or the inhaler described in European Patent Application EP 0505 321), using which an optimal administration of active compound canbe achieved.

[0288] For the treatment of dermatoses, the compounds according to theinvention are in particular administered in the form of thosemedicaments which are suitable for topical application. For theproduction of the medicaments, the compounds according to the invention(=active compounds) are preferably mixed with suitable pharmaceuticalauxiliaries and further processed to give suitable pharmaceuticalformulations. Suitable pharmaceutical formulations are, for example,powders, emulsions, suspensions, sprays, oils, ointments, fattyointments, creams, pastes, gels or solutions.

[0289] The medicaments according to the invention are prepared byprocesses known per se. The dosage of the active compounds is carriedout in the order of magnitude customary for PDE inhibitors. Topicalapplication forms (such as ointments) for the treatment of dermatosesthus contain the active compounds in a concentration of, for example,0.1-99%. The dose for administration by inhalation is customarly between0.1 and 3 mg per day. The customary dose in the case of systemic therapy(p.o. or i.v.) is between 0.03 and 3 mg/kg per day.

Biological Investigations

[0290] The second messenger cyclic AMP (cAMP) is well-known forinhibiting inflammatory and immunocompetent cells. The PDE4 isoenzyme isbroadly expressed in cells involved in the initiation and propagation ofinflammatory diseases (H Tenor and C Schudt, in “PhosphodiesteraseInhibitors”, 2140, “The Handbook of Immunopharmacology”, Academic Press,1996), and its inhibition leads to an increase of the intracellular cAMPconcentration and thus to the inhibition of cellular activation (J ESouness et al., Immunopharmacology 47: 127-162, 2000).

[0291] The antiinflammatory potential of PDE4 inhibitors in vivo invarious animal models has been described (M M Teixeira, TiPS 18:164-170, 1997). For the investigation of PDE4 inhibition on the cellularlevel (in vitro), a large variety of proinflammatory responses can bemeasured. Examples are the superoxide production of neutrophilic (CSchudt et al., Arch Pharmacol 344: 682-690, 1991) or eosinophilic (AHatzelmann et al., Brit J Pharmacol 114: 821-831, 1995) granulocytes,which can be measured as luminol-enhanced chemiluminescence, or thesynthesis of tumor necrosis factor-α in monocytes, macrophages ordendritic cells (Gantner et al., Brit J Pharmacol 121: 221-231, 1997,and Pulmonary Pharmacol Therap 12: 377-386, 1999). In addition, theimmunomodulatory potential of PDE4 inhibitors is evident from theinhibition of T-cell responses like cytokine synthesis or proliferation(D M Essayan, Biochem Pharmacol 57: 965-973, 1999). Substances whichinhibit the secretion of the afore-mentioned proinflammatory mediatorsare those which inhibit PDE4. PDE4 inhibition by the compounds accordingto the invention is thus a central indicator for the suppression ofinflammatory processes.

[0292] Method for Measuring Inhibition of PDE4 Activity

[0293] PDE4 activity was determined as described by Thompson et al. (AdvCycl Nucl Res 10: 69-92, 1979) with some modifications (Bauer andSchwabe, Naunyn-Schmiedeberg's Arch Pharnacol 311: 193-198, 1980). At afinal assay volume of 200 μl (96well microtiter plates) the assaymixture contained 20 mM Tris (pH 7.4), 5 mM MgCl₂, 0.5 pM cAMP, [³H]cAMP(about 30,000 cpm/assay), the test compound and an aliquot of cytosolfrom human neutrophils which mainly contains PDE4 activity as describedby Schudt et al. (Naunyn-Schmiedeberg's Arch Pharmacol 344: 682-690,1991); the PDE3-specific inhibitor Motapizone (1 μM) was included tosuppress PDE3 activity originating from contaminating platelets. Serialdilutions of the compounds were prepared in DMSO and further diluted1:100 (v/v) in the assays to obtain the desired final concentrations ofthe inhibitors at a DMSO concentration of 1% (v/v) which by itself onlyslightly affected PDE4 activity.

[0294] After preincubation for 5 min at 37° C., the reaction was startedby the addition of substrate (cAMP) and the assays were incubated forfurther 15 min at 37° C. 50 μl of 0.2 N HCl was added to stop thereaction and the assays were left on ice for about 10 min. Followingincubation with 25 μg 5′-nucleotidase (Crotalus atrox snake venom) for10 min at 37° C., the assays were loaded on QAE Sephadex A-25 (1 ml bedvolume). The columns were eluted with 2 ml of 30 mM ammonium formiate(pH 6.0) and the eluate was counted for radioactivity. Results werecorrected for blank values (measured in the presence of denaturedprotein) which were below 5% of total radioactivity. The amount ofcyclic nucleotides hydrolyzed did not exceed 30 % of the originalsubstrate concentration. The IC₅₀ -values for the compounds according tothe invention for the inhibition of the PDE4 activity were determinedfrom the concentration-inhibition curves by nonlinear-regression.

[0295] For the following compounds inhibitory values [measured as-logIC₅₀ (mol/l)] higher than 9 were determined. The numbers of thecompounds correspond to the numbers of the examples.

[0296] Compounds 8-15 and 18-29.

1.

in which R1 and R2 are both hydrogen or together form an additionalbond, R3 represents a benzene derivative of formula (a) or (b)

wherein R4 is 1-4C-alkoxy or 1-4C-alkoxy which is completely orpredominantly substituted by fluorine, R5 is 1-8C-alkoxy,3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxy, or 1-4C-alkoxy which iscompletely or predominantly substituted by fluorine, R6 is 1-4C-alkoxy,3-5C-cycloalkoxy, 3-5C-cycloalkylmethoxy, or 1-4C-alkoxy which iscompletely or predominantly substituted by fluorine, R7 is 1-4C-alkyland R8 is hydrogen or 1-4C-alkyl, or wherein R7 and R8 together and withinclusion of the two carbon atoms, to which they are bonded, form aspiro-linked 5-, 6- or 7-membered hydrocarbon ring, optionallyinterrupted by an oxygen or sulphur atom, A is a bond or methylene(—CH₂—), R9 is —C(O)R10, —(CH₂),—C(O)R11, —(CH₂)_(n)R12, Aryl, Hetaryl,phenylprop-1-en-3-yl or 1-methylpiperidin-4-yl, R10 hydrogen,1-4C-alkyl, —OR13, furanyl, indolyl, phenyl, pyridyl, phenyl substitutedby R16 and/or R17 or pyridyl substituted by R18 and/or R19, R11 is—N(R14)R15, R12 is —N(R14)R15, tetrahydrofuranyl or pyridinyl, R13 is1-4C-alkyl, R14 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl or3-7C-cycloalkylmethyl, R15 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl or3-7C-cycloalkylmethyl, or R14 and R15 together and with inclusion of thenitrogen atom to which they are bonded, form a 4-morpholinyl-,1-pyrrolidinyl-, 1-piperidinyl- or 1-hexahydroazepinyl-ring, Aryl isphenyl, pyridyl, pyrimidinyl, phenyl substituted by R16 and/or R17,pyridyl substituted by R18 and/or R19, R16 is halogen, nitro,1-4C-alkyl, trifluoromethyl or 1-4C-alkoxy, R17 is halogen or1-4C-alkyl, R18 is halogen, nitro, 1-4C-alkyl, trifluoromethyl or1-4C-alkoxy, R19 is halogen or 1-4C-alkyl, Hetaryl is indol-4-yl,2-methyl-quinolin-4-yl,5-chloro-6-oxo-i-phenyl-1,6-dihydro-pyridazin-4-yl,3-phenyl-1,2,4-thiadiazol-5-yl or 3-o-tolyl-1,2,4-thiadiazol-5-yl, n isan integer from 1 to 4, m is an integer from 1 to 4, s is an integerfrom 1 to 2, X is —C(O)— or —S(O)₂—, and the salts of these compounds.2. Compounds of formula I according to claim 1 in which R1 and R2 areboth hydrogen or together form an additional bond, R3 represents abenzene derivative of formula (a) or (b)

wherein R4 is 1-2C-alkoxy or 1-2C-alkoxy which is completely orpredominantly substituted by fluorine, R5 is 14C-alkoxy, R6 is1-2C-alkoxy or 1-2C-alkoxy which is completely or predominantlysubstituted by fluorine, R7 is methyl and R8 is hydrogen, or wherein R7and R8 together and with inclusion of the two carbon atoms, to whichthey are bonded, form a spiro-linked cyclopentane, cyclohexane,tetrahydrofurane or tetrahydropyran ring, A is a bond or methylene(—CH₂—), R9 is —C(O)R10, —(CH₂)_(m)—C(O)R11, —(CH₂)_(n)R12, Aryl,Hetaryl, phenylprop-1-en-3-yl or 1-methylpiperidin-4-yl, R10 hydrogen,1-4C-alkyl, —OR13, furanyl, indolyl, pyridyl or pyridyl substituted byR18 and/or R19, R11 is —N(R14)R15, R12 is —N(R14)R15, tetrahydrofuranylor pyridinyl, R13 is 1-4C-alkyl, R14 is hydrogen, 1-4C-alkyl,3-7C-cycloalkyl or 3-7C-cycloalkylmethyl, R15 is hydrogen, 1-4C-alkyl,3-7C-cycloalkyl or 3-7C-cycloalkylmethyl, or R14 and R15 together andwith inclusion of the nitrogen atom to which they are bonded, form a4-morpholinyl-, 1-pyrrolidinyl-, 1-piperidinyl- or1-hexahydroazepinyl-ring, Aryl is phenyl, pyridyl, pyrimidinyl, phenylsubstituted by R16 and/or R17, pyridyl substituted by R18 and/or R19,R16 is halogen, nitro, 1-4C-alkyl, trifluoromethyl or 1-4C-alkoxy, R17is halogen or 14C-alkyl, R18 Is halogen, nitro, 1-4C-alkyl,trifluoromethyl or 1-4C-alkoxy, R19 is halogen or 1-4C-alkyl, Hetaryl isindol-4-yl, 2-methyl-quinolin-4-yl,5-chloro-6-oxo-1-phenyl-1,6-dihydro-pyridazin-4-yl,3-phenyl-1,2,4-thiadiazol-5-yl or 3-o-tolyl-1,2,4-thiadiazol-5-yl, n isan integer from 1 to 4, m is an integer from 1 to 4, s is 1, X is —C(O)or —S(O)₂—, and the salts of these compounds.
 3. Compounds of formula Iaccording to claim 1 in which R1 and R2 together form an additionalbond, R3 represents a benzene derivative of formula (a) or (b)

wherein R4 is methoxy or ethoxy, R5 is methoxy or ethoxy, R6 is methoxy,R7 is methyl and R8 is hydrogen, or wherein R7 and R8 together and withinclusion of the two carbon atoms, to which they are bonded, form acyclopentane or cyclohexan ring, A is a bond or methylene (—CH₂—), R9 isphenyl, pyrid-2-yl, pyrid-4-yl, pyrimidin-2-yl, 3-dimethylaminopropyl,2-dimethylaminoethyl, dimethylaminocarbonylmethyl, furan-2-yl-methanoyl,fonmyl, ethoxycarbonyl, 5-nitropyridin-2-yl, 3,5-dichloropyridin-4-yl,2-(morpholin-4-yl)ethyl, 3-(morpholin-4-yl)propyl,2-morpholin-4-yl-2-oxo-ethyl, 2-oxo-2-pyrrolidin-1-yl-ethyl, 1H-indol-4-yl, tetrahydrofuran-2-ylmethyl, 2-(pyrrolidin-1-yl)-ethyl,pyridin-4-ylmethyl, 2-methyl-quinolin-4-yl, 1-methyl-piperidin-4-yl,5-trifluoromethyl-pyridin-2-yl,5-chloro-6-oxo-1-phenyl-1,6-dihydro-pyridazin-4-yl,3-phenyl-1,2,4-thiadiazol-5-yl, 3-o-tolyl-1,2,4-thiadiazol-5-yl or(E)-3-phenylallyl, s is1, X is —C(O)— or —S(O)₂—, and the salts of thesecompounds.
 4. Compounds of formula I according to claim 1 in which R1and R2 together form an additional bond, R3 represents a benzenederivative of formula (a) or (b)

wherein R4 is methoxy or ethoxy, R5 is methoxy or ethoxy, R6 is methoxy,R7 is methyl and R8 is hydrogen, A is a bond, R9 is phenyl, pyrid-2-yl,pyrid4-yl, 3-dimethylaminopropyl, 2-dimethylaminoethyl,dimethylaminocarbonylmethyl, furan-2-yl-methanoyl, formyl,ethoxycarbonyl, 5-nitropyridin-2-yl, 3,5-dichloropyridin-4-yl,2-(morpholin-4-yl)ethyl, 3-(morpholin-4-yl)propyl,2-morpholin-4-yl-2-oxo-ethyl, 2-oxo-2-pyrrolidin-1-yl-ethyl,1H-indol-4-yl, tetrahydrofuran-2-ylmethyl, 2-(pyrrolidin-1-yl)ethyl,pyridin-4-ylmethyl, 2-methyl-quinolin-4-yl, 1-methyl-piperidin-4-yl,5-trifluoromethyl-pyridin-2-yl,5chloro-6-oxo-1-phenyl-1,6-dihydro-pyridazin-4-yl,3-phenyl-1,2,4-thiadiazol-5-yl, 3-o-tolyl-1,2,4-thiadiazol-5-yl or(E)-3-phenylallyl, s is 1, X is —C(O)—, and the salts of thesecompounds.
 5. Compounds of formula I according to claim 1 in which R1and R2 together form an additional bond, R3 represents a benzenederivative of formula (b)

wherein R6 is methoxy, R7 is methyl and R8 is hydrogen, A is methylene(—CH₂—), R9 is pyrimidin-2-yl, 3-dimethylaminopropyl or2-(morpholin-4-yl)ethyl, s is 1, X is —C(O)—, and the salts of thesecompounds.
 6. Compounds of formula I according to claim 1 in which R1and R2 are both hydrogen or together form an additional bond, R3represents a benzene derivative of formula (a) or (b)

wherein R4 is 1-4C-alkoxy or 1-4C-alkoxy which is completely orpredominantly substituted by fluorine, R5 is 1-8C-alkoxy,3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxy, or 1-4C-alkoxy which iscompletely or predominantly substituted by fluorine, R6 is 1-4C-alkoxy,3-5C-cycloalkoxy, 3-5C-cycloalkylmethoxy, or 1-4C-alkoxy which iscompletely or predominantly substituted by fluorine, R7 is 1-4C-alkyland R8 is hydrogen or 1-4C-alkyl, or wherein R7 and R8 together and withinclusion of the two carbon atoms, to which they are bonded, form aspiro-linked 5-, 6- or 7-membered hydrocarbon ring, optionallyinterrupted by an oxygen or sulphur atom, A is a bond, R9 is —C(O)R10,—(CH₂)_(m)—C(O)R11, —(CH₂)_(n)R12, Aryl, Hetaryl, phenylprop-1-en-3-ylor 1-methyl-piperidin-4-yl, R10 hydrogen, 1-4C-alky, —OR13, furanyl,indolyl, phenyl, pyridyl, phenyl substituted by R16 and/or R17 orpyridyl substituted by R18 and/or R19, R11 is —N(R14)R15, R12 is—N(R14)R15, tetrahydrofuranyl or pyridinyl, R13 is 1-4C-alkyl, R14 ishydrogen, 1-4C-alkyl, 3-7C-cycloalkyl or 3-7C-cycloalkylmethyl, R15 ishydrogen or 1-4C-alkyl, 3-7C-cycloalkyl or 3-7C-cycloalkylmethyl, or R14and R15 together and with inclusion of the nitrogen atom to which theyare bonded, form a 4-morpholiny-, 1-pyrrolidiny-, 1-piperidinyl- or1-hexahydroazepinyl-ring, Aryl is phenyl, pyridyl, phenyl substituted byR16 and/or R17, pyridyl substituted by R18 and/or R19, R16 is halogen,nitro, 1-4C-alkyl, trifluoromethyl or 1-4C-alkoxy, R17 is halogen or 14C-alkyl, R18 is halogen, nitro, 1-4C-alkyl, trifluoromethyl or1-4C-alkoxy, R19 is halogen or 1-4C-alkyl, Hetaryl is indol4-yl,2-methyl-quinolin4-yl, 5-chloro-6-oxo-1-phenyl-1,6-dihydro-pyridazin4-ylor 3-phenyl-1,2,4-thiadiazol-5-yl, n is an integer from 1 to 4, m is aninteger from 1 to 4, s is an integer from 1 to 2, X is —C(O)— or—S(O)₂—, and the salts of these compounds.
 7. Compounds of formula Iaccording to claim 1 in which R1 and R2 are both hydrogen or togetherform an additional bond, R3 represents a benzene derivative of formula(a) or (b)

wherein R4 is 1-2C-alkoxy or 1-2C-alkoxy which is completely orpredominantly substituted by fluorine, R5 is 1-4C-alkoxy, R6 is1-2C-alkoxy or 1-2C-alkoxy which is completely or predominantlysubstituted by fluorine, R7 is methyl and R8 is hydrogen, or wherein R7and R8 together and with inclusion of the two carbon atoms, to whichthey are bonded, form a spiro-linked cyclopentane, cyclohexane,tetrahydrofurane or tetrahydropyran ring, A is a bond, R9 is —C(O)R10,—(CH₂)_(m)—C(O)R11, —(CH₂)_(n)R12, Aryl, Hetaryl, phenylprop-1-en-3-ylor 1-methyl-piperidin-4-yl, R10 hydrogen, 1-4C-alkyl, —OR13, furanyl,indolyl, pyridyl or pyridyl substituted by R18 and/or R19, R11 is—N(R14)R15, R12 is —N(R14)R15, tetrahydrofuranyl or pyridinyl, R13 is1-4C-alkyl, R14 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl or3-7C-cycloalkylmethyl, R15 is hydrogen or 1-4C-alkyl, 3-7C-cycloalkyl or3-7C-cycloalkylmethyl, or R14 and R15 together and with inclusion of thenitrogen atom to which they are bonded, form a 4-morpholinyl-,1-pyrrolidinyl-, 1-piperidinyl- or 1-hexahydroazepinyl-ring, Aryl isphenyl, pyridyl, phenyl substituted by R16 and/or R17, pyridylsubstituted by R18 and/or R19, R16 is halogen, nitro, 1-4C-alkyl,trifluoromethyl or 1-4C-alkoxy, R17 is halogen or 1-4C-alkyl, R18 ishalogen, nitro, 1-4C-alkyl, trifluoromethyl or 1-4C-alkoxy, R19 ishalogen or 1-4C-alkyl, Hetaryl is indol-4-yl, 2-methyl-quinolin-4-yl,5-chloro-6-oxo-1-phenyl-1,6-dihydro-pyridazin-4-yl or3-phenyl-1,2,4-thiadiazol-5-yl, n is an integer from 1 to 4, m is aninteger from 1 to 4, s is 1, X is —C(O)— or —S(O)₂—, and the salts ofthese compounds.
 8. Compounds of formula I according to claim 1 in whichR1 and R2 together form an additional bond, R3 represents a benzenederivative of formula (a) or (b)

wherein R4 is methoxy or ethoxy, R5 is methoxy or ethoxy, R6 is methoxy,R7 is methyl and R8 is hydrogen, or wherein R7 and R8 together and withinclusion of the two carbon atoms, to which they are bonded, form acyclopentane or cyclohexan ring, A is a bond, R9 is phenyl, pyrid-2-yl,dimethylaminopropyl, dimethylaminoethyl, furan-2-yl-methanoyl, formyl,ethoxycarbonyl, 5-nitropyridin-2-yl, 3,5-dichloropyridin4-yl,2-(morpholin-4-yl)ethyl, 3-(morpholin-4-yl)propyl, indol-4-yl,tetrahydrofuran-2-ylmethyl, 2-(pyrrolidin-1-yl)ethyl,pyridin-4-ylmethyl, 2-methyl-quinolin-4-yl, 1-methyl-piperidin-yl,5-trifluoromethyl-pyridin-2-yl,5-chloro-6-oxo-1-phenyl-1,6-dihydro-pyridazin-4-yl,3-phenyl-1,2,4-thiadiazol-5-yl or phenylprop-1-en-3-yl, s is 1, X is—C(O)— or —S(O)₂—, and the salts of these compounds.
 9. Compounds offormula I according to claim 1 in which R1 and R2 together form anadditional bond, R3 represents a benzene derivative of formula (a) or(b)

wherein R4 is methoxy or ethoxy, R5 is methoxy or ethoxy, R6 is methoxy,R7 is methyl and R8 is hydrogen, A is a bond, R9 is phenyl, pyrid-2-yl,dimethylaminoethyl, dimethylaminopropyl, furan-2-yl-methanoyl, formyl,ethoxycarbonyl, 5-nitropyridin-2-yl, 3,5-dichloropyridin-4-yl,2-(morpholin-4-yl)ethyl,5-chloro-6-oxo-1-phenyl-1,6-dihydro-pyridazin-4-yl,3-phenyl-1,2,4-thiadiazol-5-yl or phenylprop-1-en-3-yl, s is 1, X is—C(O)— or —S(O)₂—, and the salts of these compounds.
 10. Compounds offormula I according to one of the claims 1 to 8 in which the hydrogenatoms in the positions 4a and 8a are cis-configurated.
 11. Compounds offormula I according to one of the claims 1 to 8 in which the absoluteconfiguration (according to the rules of Cahn, Ingold and Prelog) is Sin the position 4a and R in the position 8a.
 12. Compounds of formula Iaccording to claim 1 for the treatment of diseases.
 13. Medicamentscontaining one or more compounds of formula I according to claim 1together with the usual pharmaceutical auxiliaries and/or carriermaterials.
 14. Use of compounds of formula I according to claim 1 forthe preparation of medicaments for the treatment of airway disorders.